• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

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• Q. Define Turner syndrome

  • Gravholt et al. define Turner syndrome as "Turner syndrome is a rare condition in women that is associated with either complete or partial loss of one X chromosome, often in mosaic karyotypes ^[1]

• Q. What is the result of mitotic division and meiotic division?

  • Mitosis leads to the development of two daughter cells which are identical to the parent cell and are diploid
  • Meiosis goes to two rounds of division to produce four daughter cells which are haploid. There is a cross over and recombination of genetic information leading to the development of daughter cells which are different from the parent cells

• Q. What are the phases of mitosis?

  • PMAT- Prophase, metaphase, anaphase, and telophase

• Q. What are the two rounds in Meiosis?

  • The first round is reduction division, and the second round keeps the same number as in mitosis

• Q. At what phase do the chromosome defects mainly occur?

  • They mainly occur in the anaphase

• Q What is non-disjunction?

  • Failure of sister chromatids to separate

• Q. Broadly, what are the types of chromosomal abnormalities?

  • Chromosomal abnormalities
  • Abnormality in number - aneuploidy or polyploidy
  • Abnormality in structure – Deletion, duplication, inversion, etc

• Q. What is aneuploidy?

  • Aneuploidy means there is one chromosome extra compared to usual or one chromosome less
  • Trisomy – means extra chromosome, monosomy means one less chromosome

• Q. What is polyploidy?

  • Polyploidy is an incremental number of chromosomes in sets – instead of 2 pairs – we have four pairs of chromosome

• Q. What are the causes of aneuploidy?

  • Meiotic non-disjunction- can occur in both phases of meiosis
  • Mitotic non-disjunction – occurs in anaphase of mitosis
  • Chromosomal translocations

• Q. What are collecting system abnormalities?

  • Abnormalities in the ureter- 2 ureters joining bladder, etc

• Q. What is hypertelorism?

  • Increase the distance between the eyes

• Pathogenesis of Turner syndrome

• Q. What is the reason behind the chromosomal abnormality of Turner’s?

  • Genetics: Chromosomal Origins
  • Most commonly due to error(s) of recombination and segregation occurring during meiotic divisions
  • Less commonly due to non-disjunction in early embryonic mitotic cell divisions
    • (e.g., 45,X/47,XXX; 45,X/46,XX; 45,X/46,XY)
  • Molecular triggers are poorly understood
  • Not preferentially linked to maternal meiotic errors or age and may be more commonly associated with paternal meiotic errors
  • 

• Q. Summarize the various Karyotypes seen in Turner?

  • 

• Q. What are the features of XP and Xq deletion?

  • Xp deletion- Short stature without Premature ovarian insufficiency (POI)
  • Xq deletion – POI without short stature

• Q. What are the genes implicated in Short stature and gonadal insufficiency?

  • Short stature- SHOX gene on pseudoautosomal region of Xp
  • Gonadal insufficiency
    • FMR1 and FMR2 on Xq
    • BMP15- Xp

• Q. What are the consequences of intrauterine lymphedema?

  • Pressure effect from the Lymphedema contributes to
  • Webbed neck
  • Renal abnormalities
  • Shield chest
  • Ear malformations
  • Certain cardiac defects

• Clinical features of Turner syndrome

• Q. What are the Clinical features of Turner noticeable in neonates?

  • Congenital Lymphedema of hands and feet
  • Short 4th and metatarsal
  • Narrow and High arched palate
  • Nail dysplasia

• Q. Give the Clinical features in a child with Turner syndrome – from head to toe?

  • 

• Q. What kind of neurocognitive problems are common?

  • Visual-spatial orientation issues
  • Poor arithmetic skills

• Q. Which cardiac lesions are common in Turner’s syndrome?

  • Left-sided cardiac lesions are common
  • Bicuspid aortic valve is the commonest- present in 30-50% of patients
  • Coarctation of the aorta – present in 30% of patients

• Q. Which is the most dreaded cardiac complication?

  • Aortic root rupture/dissection due to aortic root dilatation is the most dreaded complication

• Q. Is there any evidence of using a Prophylactic beta-blocker for aortic root dilatation?

  • No solid evidence to recommend beta-blocker use
  • However, patients with hypertension and resting tachycardia may benefit from beta-blocker therapy

• Q. Which other cardiac abnormalities are seen?

  • Partial anomalous pulmonary venous connection
  • Peristent left superior vena cava

• Q. Congenital lymphedema present at birth in patients with Turner’s syndrome is resolved by what age?

  • Generally resolves by two years of age
  • Can recur at a later date in adulthood
  • Lymphedema

• Q. Which is the most common urinary system abnormality?

  • Collecting system malformations – most common – more common with Mosaic turner’s
  • Horseshoe kidney – 2nd most common - often seen in 46 X0

• Q. What are the abnormalities in the eyes?

  • Epicanthal folds
  • Ptosis
  • Hypertelorism
  • Hyperopia
  • Upward slanting palpebral fissures
  • High risk of amblyopia
  • Strabismus
  • Red-green color deficiency

• Q. Why is otitis media more common in Turner’s patients?

  • There is an abnormal cranial base anatomy
  • Hence there is an abnormal relationship between the eustachian tube and the middle ear
  • Hence increased risk of Otitis media

• Q. What is the other cause of deafness in Turner’s patient?

  • Progressive sensorineural hearing loss
  • Dip at 1.5-2 Hz, and often frequencies above 8 Hz are not heard

• Q. What type of face is typical of Turner’s?

  • Retrognathic face

• Q. How early is autoimmune thyroid disease seen in patients with Turner’s syndrome?

  • As early as four years of age
  • So screen for thyroid annually starting from 4 years of age

• Q. When is the growth delayed in Turner’s?

  • The growth is delayed right from the beginning
  • There is a mild intrauterine growth retardation
  • Delayed growth during childhood
  • Absence of pubertal growth spurt
  • Overall, adult height is lost by 20 cm compared to normal peer

• Q. What % of patients with Turner’s have spontaneous Pubertal development?

  • 30%

• Q. Enlist the skeletal abnormalities in Turner?

  • Retrognathia
  • Short neck
  • Short 4th metacarpal and metatarsal
  • Cubitus valgus
  • Madelung deformity
  • Mesomelia
  • Kyphosis – 50%
  • Scoliosis in 30%
  • Genu valgus
  • Genu varum
  • Congenital dislocation of the hip

• Q. What are biochemical markers of ovarian failure in Turner’s?

  • Raised FSH
  • Reduced AMH

• Q. The ovarian follicles in Turner are they always absent, or do they degenerate faster?

  • Up to 6 weeks of life, the ovarian follicles are normal
  • Then, they start to undergo ACCELERATED APOPTOSIS
  • The critical problem in Turner has accelerated apoptosis and no absent ovarian follicles per se
  • The rate of ovarian follicle apoptosis is variable, which explains the variable reproductive features of Turner’s
  • Both normal X chromosomes are required for ovarian survival

• Q. Which two important clinical features are an important marker of possible CVS problems in Turner?

  • Presence of Webbed neck
  • Increase AP diameter of the chest

• Q. CV abnormalities are more in 45 XO or Mosaic turner?

  • 45 XO

• Q. Which patients have an increased risk of aortic dissection?

  • Those having Aortic size index > 2 cm/m2
  • Hypertension
  • Coarctation of the aorta
  • Bicuspid aortic valve

• Q. Aortic dissection at what age in Turner?

  • 3rd to 4th decade
  • During pregnancy

• Q. Why do Turner patients have an increased risk of CAD?

  • Loss of protection from estrogen dyslipidemia, atherosclerosis
  • Pre-existing CV lesions
  • Turner’s patients have a form of vasculopathy
  • Increased risk of diabetes and metabolic syndrome

• Q. What are the reasons for osteoporosis in Turner?

  • Underestimation of BMD because of small size
  • Lack of estrogen
  • Intrinsic microstructural abnormalities of the bone

• Q. Do patients with Turner have an increased risk of Cancer?

  • Y chromosome material- Gonadoblastoma
  • Increased risk of other cancers – have been reported by some

• Q. Which autoimmune and related disorders are common in Turner?

  • Hypothyroidism
  • Celiac disease
  • Inflammatory bowel disease

• Q. What kind of liver abnormality is seen?

  • Transaminitis corrects with the administration of estrogen

• Q. Which benign neoplasm of skin is characteristic of Turner?

  • PLICOMATRICOMA

• Q. Which another skin lesion is characteristic?

  • Pigmented nevi are common in Turner
  • However, the risk of melanoma is NOT increased; in fact, maybe reduced

• Q What is Atypical Turner’s?

  • If the X inactivation site is missing – XIST, these patients with Ring X chromosome have atypical Turner syndrome having
  • Mental Retardation
  • Syndactyl
  • Severe short stature
  • Facial dysmorphism

• Q. What features on Prenatal ultrasound prompt an investigation for Turner?

  • Increase nuchal translucency
  • Short femur length
  • Septated cystic hygroma
  • Cardiovascular abnormalities
  • Lymphectasia- fetal hydrops

• Q. How is the diagnosis made prenatally?

  • Karyotype from fetal cells obtained by amniocentesis or CVS
  • Must be confirmed at birth with neonatal blood

• Q. What are indications for screening for Turner at various age groups?

  • Infancy – the presence of congenital lymphedema
  • Children
  • Characteristic phenotype
  • Growth failure
  • 3. Adolescent – primary or secondary amenorrhea
  • 4. Adult – POI

• Q. What is the investigation of choice in Turner?

  • Karyotype obtained from peripheral blood

• Q. How many cells must be tested?

  • American college of genetic medicine suggests 30 cell lines to diagnose Mosaicism

• Q. What are other means of diagnosis of mosaicism?

  • FISH- 60% cases it diagnosis
  • PCR – 74% successful

• Q. What is done if Turner is strongly suspected and peripheral blood karyotype is normal?

  • Repeat karyotype from skin biopsy

• Q. Which is a new test that is developed, which can potentially help in screening for Turner at birth?

  • High throughput pyrosequencing tests for 18 SNP in X chromosome and one in Y chromosome to look for possible Turner
  • This has potential use in widespread screening

• Q. What percentage of Turner patients have Y chromosome material?

  • 10%

• Q. in which patient is search for Y chromosome made?

  • Presence of unidentified chromosomal material on karyotype called MARKER CHROMOSOME ELEMENTS
  • Features of androgenization in Turner patient
  • Routine search for Y in all patients is not useful

• Q. How is Y chromosome material looked for?

  • Using FISH

• Q. What is done if Y is found?

  • Prophylactic gonadectomy to reduce risk of gonadoblastoma
  • Management of Turner syndrome

• Q. Give the overview of the management of Turner in children?

  • Following things need to be considered
  • 1. Management of Cardiovascular system
  • 2. Estrogen therapy
  • 3. Short stature – evaluation and therapy
  • 4. Management of other abnormalities

• Q. What is the baseline cardiac evaluation?

  • Baseline evaluation
    • 1. All four limb blood pressure measurement
    • 2. ECG at baseline
    • 3. Echocardiography at baseline
    • 4. Older girls and adults also need to get done cardiac/thoracic MRI (At age ten years)
    • 5. If anything abnormal- refer to a cardiologist
    • 6. If everything is normal – follow up

• Q. What is the definition of hypertension in children?

  • Normal <90th centile BP
  • Pre-hypertension
    • ≥90th-<95th centile
    • ≥120/80 mm Hg (even if <90th centile)t
  • Stage I hypertension 95th-99th centile plus 5 mm Hg
  • Stage I hypertension >99th centile plus 5 mm Hg

• Q. What tests are done on follow-up for CV evaluation?

  • Follow up :
  • 1. All four limb BP measurements in every visit
  • 2. Regular aortic root diameter monitoring on Echocardiography
  • 3. Repeat Cardiac MRI indicated if
    • a. Patient develops hypertension
    • b. Achieves adulthood
    • c. Every five years
    • d. Planning pregnancy

• Q. Describe the management of hypertension in Turner syndrome?

  • 

• Q. What is the indication for Growth hormone (GH) therapy in Turner syndrome?

  • GH therapy in Turner syndrome is indicated when height falls below the 5th percentile of NORMAL FEMALE on the growth chart
  • This usually occurs between 2-5 years in Turner’s patients

• Q. What is the mode of therapy for short stature in Turner syndrome?

  • Mode of therapy
    • a. Age < 9years- Growth Hormone
    • b. Age > 9 yrs – Growth hormone and Oxandrolone

• Q. What is the dose of GH used in Turner syndrome?

  • Growth hormone
  • Dose is 0.375 mg/kg/wk (50 microgram/kg/day)

• Q. What is the dose of Oxandrolone?

  • Oxandrolone
  • Dose : 0.05 mg/kg/day
  • T. Oxandrin is the brand - Available at 2.5 and 10 mg tablets – given in 2-4 divided doses
  • Regular liver function test monitoring required

• Q. How long is the therapy continued?

  • Till growth potential remains
    • a. Bone age >14 years
    • b. Growth velocity <2 cm / year

• Q. Describe the protocol for Pubertal induction in Turner syndrome?

  • Age of 12 years (Note: Remember it is bone age of 12 years and not chronological age of 12 years )
  • a. Start estrogen therapy
  • b. Micronized 17 beta-estradiol preferred
    • T. PROGYNOVA 0.5 mg (1/2 tablet) on alternate days. (1/8th of Adult dose)
    • If Progynova is not available, then Conjugated estrogen - T. PREMARIN – 0.625 mg once a day may be given as an alternative.
    • i. T Progynova- increase by ½ tablet (0.5 mg) every six months till adult dose of 2 mg is reached
    • ii. T. Premarin - increase by ½ tablet (0.3 mg) every six months till adult dose of 1.25 mg
    • Premarin- Conjugated estrogen – 0.625 mg = Progynova 1 mg (Estradiol valerate – prodrug of 17 beta estradiol)

• Q. When are progestins added?

  • Progesterone started two years after starting estrogen or when breakthrough bleeding occurs
  • Age of 14 years
  • a. Patient now receives an adult dose of Estrogen. Estrogen is generally given from days 1-25.
  • b. Progesterone may be added cyclically (may be added earlier if breakthrough bleeding occurs)
  • i. C. ALGEST / ENDOGEST – 200 mg on day 20-30 of cycle
  • ii. T. MEPRATE (Medroxyprogesterone) –2.5- 5 mg on days 20-30

• Q. Describe the sex steroid management after puberty is induced and in adulthood?

  • 15-30 years of age
    • Continue the above therapy
    • If Cost is an issue, then OCP may be used – T. DIANE 35 (35 micrograms of Ethinyl estradiol) – however, not preferred
  • 30- 50 years
    • Give the lowest dose of estrogen- T. PREMARIN 0.625 mg once a day
  • 50 years( postmenopausal)
    • Management, like any other postmenopausal women

• Q. Outline the management of Turner in Adults?

  • Cardiovascular system (See earlier)
  • Estrogen therapy (See earlier)
  • Endocrine and related problems
    • Hypothyroidism – Annual screening required
    • Celiac disease- screen evert 2- 5years
    • Metabolic syndrome
    • Fertility
    • Osteoporosis
    • Other issues
  • Annual liver function test

• Q. Describe the fertility options for Turner?

  • Women with functional ovaries- early pregnancy or oocyte/embryo cryopreservation
  • Women without functional ovaries- oocyte or embryo donation

• Q. What are the complications anticipated during pregnancy?

  • Risk of aortic dissection and rupture- dreaded complication
  • Hypertension
  • Diabetes
  • Small size- more chance of LSCS

• Q. What should the size of endometrium be before implantation of donor oocyte or embryo?

  • At least 7 mm

• Q. Describe the osteoporosis management in Turner?

  • Osteoporosis management
  • BMD must be done on the first visit with an adult doctor
  • If BMD is normal – then re-evaluation is done once the estrogen therapy stops
  • If BMD is abnormal – treated according to osteoporosis protocol

• Q. Which is the preferred antihypertensive in Turner syndrome?

  • Beta-blockers
  • Sex chromosome abnormality

• Q. What is aneuploidy?

  • Numerical abnormality in a chromosome is called aneuploidy

• Q. What are the feature of 46 XYY?

  • They are of tall stature
  • Normal puberty
  • May have a mild motor and developmental delays but otherwise are more or less normal

• Q. Which is the MC sex chromosomal abnormality in females?

  • 46 XXX

• Q. What are the features of 46 XXX?

  • Taller than normal
  • May have POI
  • May have mild developmental delay and lower IQ

• Q. What are the feature of 49 XXXXY?

  • It is considered a variant of Kleinfelter but is more severe
  • Severe hypogonadism, developmental delays, radioulnar synostosis, a low nasal bridge with upturned nose

• Q. Which disease does 49, XXXXX resemble?

  • This is called pentasomy X
  • It resembles Downs syndrome

• Q. What is 45 X/46 XX?

  • It is a form of mosaic turner
  • It is commonly diagnosed on antenatal karyotype on amniocentesis

• Q. What about 45 X/46 XY?

  • This produces mixed gonadal dysgenesis
  • Bicuspid aortic valve

• Q. Which is more likely to occur with bicuspid aortic valve- stenosis or regurgitation?

  • Aortic stenosis is more likely to occur

• Q. What are other complications associated with the bicuspid aortic valve?

  • Bicuspid aortic valve is a marker of underlying vasculopathy
  • Hence they are at higher risk of developing:
  • Aortic root dilatation
  • Aortic dissection

• Q. Which are other cardiac complications accompanying the bicuspid aortic valve?

  • Coarctation of the aorta
  • Subvalvular or supravalvular aortic stenosis
  • VSD
  • Sinus of Valsalva aneurysm

• Q. What is the auscultation finding of a functionally standard bicuspid aortic valve?

  • Brief ejection click at apex, aortic area
  • With mild ejection systolic murmur

• Q. What about valve associated with dysfunction?

  • AS- Diamond-shaped ejection systolic murmur
  • AR- Diastolic Decresendo murmur

• Q. What is the most common cause of AS in children?

  • Bicuspid aortic valve

• Q. Is AS in children symptomatic?

  • It is generally asymptomatic in children
  • More severe and critical AS presents in infancy itself and have heart failure

• Q. Is antibiotic prophylaxis for bacterial endocarditis prevention recommended in patients with bicuspid aortic valve?

  • No
  • “Although the patient with bicuspid aortic valve is at risk for endocarditis, antibiotic prophylaxis is not recommended for the isolated bicuspid aortic valve.”

• Q. What are the Clinical features of Coarctation of the aorta (COA)?

  • Infants with COA- if associated with PDA – asymptomatic if PDA is closed – heart failure
  • Children- often asymptomatic
  • Adults
  • Hypertension
  • Claudication of extremities
  • Increase the risk of intracranial aneurysm

• Q. What are two classical clinical signs of COA?

  • Lower limb BP < upper limb BP
  • Radiofemoral delay

• Q. True or false, all girls with COA must be tested for Turner?

  • True

• Q. What are classical signs of COA on X-ray?

  • Infants with severe COA- Cardiomegaly with increase pulmonary vascular markings
  • Older children
  • Rib notching
  • Classical three sign with – indentation of aortic wall at the site of coarctation with dilatation above and below it

• Q. How does the location of COA determine physical examination findings?

  • If the origin of the left subclavian is proximal to the CO - then pulse and pressure in Upper limb >> Lower limb
  • If the origin of the left subclavian is beyond the COA- then the left subclavian pulse and BP will be like the lower limb and will be less than the pulse and BP in the right upper limb
  • If the origin of both the right and left subclavian is distal to the COA- then all four limbs will have an equal pulse and BP

• Q. What is a cardiac examination finding?

  • Most cases normal, at least in the precordium
  • May have associated bicuspid aortic valve- ejection click + ESM
  • Collateral- continuous mechanical murmur present
  • May have ejection systolic murmur radiating to the paravertebral region

• Q. Is it true that adults with COA are more likely to have an intracranial aneurysm?

  • True

• Q. Enlist the Differential diagnosis of short stature with delayed puberty in girls?

  • Turner syndrome
  • CDGP
  • GHD
  • MPHD
  • Other causes of hypopituitarism
  • Hypothyroidism
  • Systemic illness
  • Cushing’s syndrome

• Q. What is the birth weight of Turner children born at term?

  • Weight deficit of 600 grams in 90% of cases
  • Low birth weight- <2 SD in 20% of neonates

• Q. What is the definition of LBW in India?

  • LBW is <2.5 kg irrespective of the gestational age

• Q. What is the age at which children with Turner have maximum growth deficit?

  • They have a maximum growth deficit by 14 years of age
  • This is because after this – even though the child does not have puberty- the epiphysis does not close, so the child continues to grow

• Q Is estrogen necessary only for growth in the peripubertal period?

  • No
  • Small amount of estrogen is produced by the prepubertal ovary that contributes to the growth of a child by the generation of IGF1
  • This is absent in a child with Turner syndrome

• Q. What should be considered if a girl with Turner is short on Turner's specific chart also?

  • Consider
  • Celiac disease
  • Hypothyroidism
  • GH deficiency –seen in 10% of girls with Turner syndrome

• Q. Why do girls with Turner have lymphedema?

  • Due to maldevelopment of lymphatics due to haploinsufficiency of X chromosome.

• Q. Why do they have CoA and bicuspid aortic valves?

  • Maldevelopment of lymphatics of the Jugular chain leads to cystic hygroma- may compress on the growing cardiac structures
  • Haploinsufficiency of X chromosome

• Q. Why do they develop webbed necks?

  • In the later part of gestation, jugular lymphatic channels may open up, which may cause resolution of the cystic hygroma
  • The remnant of this produces Webbed neck

• Q. What is Telecanthus?

  • “Telecanthus (from the Greek word "tele" (τῆλε) meaning far, and the Latin word canthus, meaning either corner of the eye, where the eyelids meet) refers to the increased distance between the medial canthi of the eyes, while the inter-pupillary distance is normal.”
  • ^[2]
  • This is also seen in Turner

• Q. What is the prevalence of Celiac disease in South India?

  • “The prevalence of celiac disease in southern India is not known. Anecdotal experience of physicians and gastroenterologists in southern India suggests that it is very infrequent in southern India.”
  • ^[3]

• Q. What are points to take in history for a child with celiac disease?

  • Abdominal pain
  • Nausea and Vomiting
  • Diarrhea
  • Steatorrhea
  • Anorexia
  • Not gaining weight
  • Failure to thrive
  • May give a history that symptoms exacerbated by taking diet containing gluten (or wheat)

• Q. What are CF of Normal Adrenarche?

  • In Mid childhood
  • Appearance of pubic hair
  • Appearance of acne
  • Mild growth acceleration
  • Adult type body odor
  • Change in skin complexion of the child

• Q. How to assess for mesomelia as seen in SHOX deficiency?

  • Two ratios
    • Extremities to trunk ratio
    • Sitting height to total height ratio
  • Extremities to trunk ratio
    • Sum of leg length + Arm span divided by sitting height if it is less than 1.95 + 0.5 x height- it is suggestive of SHOX
  • Sitting height to total height ratio
    • Increase sitting height to total height is suggestive of SHOX

• Q. What is the definition of a high arch palate?

  • Subjective- see the height of palate at the first permeant molar- if the height of the palate is greater than twice the height of the teeth- it is called High arch palate
  • Objective - eight of the palate more than 2 SD above the mean